The long term research objective is to produce lipophilic penicillins or cephalosporins capable of crossing the blood-brain barrier. Such drugs will be valuable in the treatment of meningitis, particularly those caused by H. influenza, N. Meningiditis, or certain groups of streptococci in neonates. They would constitute a new class of antibiotic and attract the immediate attention of several ethical pharmaceutical manufacturers. During Phase II the applicant would enter a development agreement with one such corporation. The Phase I objectives are to prepare analogs of penicillin G in which its phenylacetate moiety is replaced by 5-methyl resorcinol, 5-pentadecyl-resorcinol, 5-heneicosylresorcinol, 6-n-heneicosyl-4-hydroxy-pyran-2-one, and 5-pentadecylphenol, compounds which render membranes permeable to certain ions and small molecules. In all cases, the phenoxyacetate of each of the above compounds will be synthesized and these then coupled to 6-amino-penicillanic acid. The antibiotic potency of the penicillin analogs will be tested against both lactamase positive and negative strains of the agents causing meningitis. Preliminary toxicity studies will be conducted in mice injected with graded amounts of the lipophilic penicillins. The mouse brains will be extracted to determine the levels of "resorcinolic" antibiotics present relative to control penicillins or cephalosporins.